Injection-site pain (ISP) is a commonly reported subjective side effect with the subcutaneous (SC) administration of biological agents, yet it may only be a concern to some. |
Multiple factors, including those related to product formulation (e.g. pH, volume, excipients, injection process) and to the patient (low body weight, gender and age) have the potential to contribute to ISP.
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While total elimination of ISP remains unlikely, it can be minimised by helping the patient develop a competent injection technique and by lowering their treatment-related anxieties. |
Other interventions to help minimise ISP include psychological interventions, allowing biologics to reach room temperature prior to injection, using the injection device most suitable for the individual patient and selecting an alternative drug formulation, when available. |
Productive patient–physician communication remains important in order to support and optimise treatment experience and adherence, while also providing the opportunity for patients to discuss any ISP-related issues. |
Digital Features
Introduction
Factors Contributing to SC ISP
Product-related factors | Injection-related factors | Patient-related factors |
---|---|---|
• Needle gauge size [44] | • Fluid viscosity [55] • Injection frequency [61] • Injection site [35] | • Low body weight [68] • Pain catastrophising [72] • Female gender [67] • Fibromyalgia [67] • Depression [67] • Severe rheumatoid arthritis [67] • Patient movement (during injection) [87] |
Product-Related Factors Contributing to SC ISP
a) | |||||||
---|---|---|---|---|---|---|---|
Product-related factors contributing to SC ISP | Humira (concentrated) (adalimumab) [90] | Humira (classic) (adalimumab) [90] | Imraldi (SB5) [91] | Amgevita (ABP 501) [92] | Idacio (MSB11022) [93] | Hulio (FKB327) [94] | Hyrimoz (GP2017) [95] |
Citrate | No | Yes | Yes | No | Yes | No | Yes |
Needle gauge | AI: 29 PFS: 29 | AI: 27 PFS: 27 | AI: 29 PFS: 29 | AI: 27 PFS: 29 | PFS: 29 PFP: 29 | PFS: 29 PFP: 29 | PFS: 27 PFP: 27 |
Latex | No | Yes | No | Yes | No | No | Yes |
pH | 5.2a | 5.2 | 5.2 | 5.2 | 5.2 | 5.2 | 5.2 |
Volume (mL) for 40 mg injection | 0.4 | 0.8 | 0.8 | 0.8 | 0.8 | 0.8 | 0.8 |
Complete formulation | • Mannitol • Polysorbate 80 • Water for injection | • Mannitol • Polysorbate 80 • Citric acid monohydrate • Disodium phosphate dihydrate • Sodium chloride • Sodium citrate • Sodium dihydrogen phosphate dihydrate • Sodium hydroxide (for pH adjustment) • Water for injection | • Sorbitol • Polysorbate 20 • Citric acid monohydrate • Histidine • Histidine hydrochloride monohydrate • Sodium citrate • Water for injection | • Sucrose • Polysorbate 80 • Glacial acetic acid • Sodium hydroxide (for pH adjustment) • Water for injection | • Mannitol • Polysorbate 80 • Citric acid monohydrate • Disodium phosphate dihydrate • Sodium chloride • Sodium citrate • Sodium dihydrogen phosphate dihydrate • Sodium hydroxide (for pH adjustment) • Water for injection | • Sorbitol (E420) • Polysorbate 80 • Methionine • Monosodium glutamate • Hydrochloric acid (for pH adjustment) • Water for injection | • Mannitol • Polysorbate 80 •
Adipic acid •
Citric acid monohydrate
•
Sodium chloride
•
Hydrochloric acid (for pH adjustment)
•
Sodium hydroxide (for pH adjustment)
•
Water for injection |
b) | ||||||
---|---|---|---|---|---|---|
Product-related factors contributing to SC ISP | Enbrel (etanercept) [96] | Benepali (SB4) [97] | Erelzi (GP2015) [98] | Nepexto (YLB113) [99] | ||
Citrate | No | No | Yes | Yes | ||
Needle gauge | PFP: 27 PFS: 27 | PFP: 27 PFS: 27 | PFP: 27 PFS: 27 | PFP: 27 PFS: 27 | ||
Latex | Yes | No | No | No | ||
pH | 6.3 | 6.2 | 6.3 | 6.3 | ||
Volume (mL) for 50 mg injections | 1.0 | 0.98 | 1.0 | 1.0 | ||
Complete formulation | • Mannitol • Sucrose • Trometamol • Sodium phosphate monobasic dihydrate • Sodium phosphate dibasic dihydrate • Sodium chloride • L-arginine hydrochloride • Water for injection | • Sucrose • Sodium dihydrogen phosphate monohydrate • Disodium hydrogen phosphate heptahydrate • Sodium chloride • Water for injection | • Sucrose • Citric acid anhydrous • Sodium citrate dihydrate • Sodium chloride • L-lysine hydrochloride • Sodium hydroxide (for pH adjustment) • Hydrochloric acid (for pH adjustment) • Water for injection | • Glycine • Sucrose • Sodium citrate • Sodium dihydrogen phosphate dihydrate • Sodium chloride • Water for injection |
pH
Buffers
Volume
Other Excipients
Needle
Device Type
Injection Process-Related Factors Contributing to SC ISP
Injection Speed and Fluid Viscosity
Injection Angle/Technique
Frequency of Injection
Injection Site
Temperature of Biologic Solution
Hypersensitivity
ISP from the Patient’s Perspective (Patient-related ISP)
Challenges in Assessing ISP
Biologic agent | Type of agent | Indication | Study duration (weeks) | ISP, % (n/N) or reporting rate (n/N) | References |
---|---|---|---|---|---|
Studies | |||||
Adalimumab | Anti-TNF | Psoriasis | 12 | 6.7 (3/45) | Gordon et al. [100] |
Adalimumab | Anti-TNF | RA | 24 | 11.3 (36/318) | Furst et al. [101] |
Adalimumab | Anti-TNF | CD | 56 | 1.9 (5/261) | Colombel et al. [102] |
Galcanezumab | Humanised mAb (CGRP) | Chronic headache | 12 | 11.1 (13/117) | Dodick et al. [103] |
Glatiramer acetate | Immunomodulator | RRMS | 16 | 56.5 (61/108)b | Wolinsky et al. [104] |
Insulin | Hormone | Diabetes | 0.14 (1 day) | 16.5 (13/79) | Zijlstra et al. [34] |
Mepolizumab | Humanised mAb (IL-5) | Asthma | 8 | 64 (36/56) | Bel et al. [105] |
Spontaneous reports | |||||
Adalimumaba | Anti-TNF | Psoriasis | ns | 3650/15637 | Grace et al. [106] |
Etanercepta | Anti-TNF | Psoriasis | ns | 23/141 | Grace et al. [106] |
Ixekizumaba | Humanised mAb (IL-17) | Psoriasis | ns | 350/1771 | Grace et al. [106] |
Secukinumaba | Humanised mAb (IL-17) | Psoriasis | ns | 166/654 | Grace et al. [106] |
Ustekinumaba | Humanised mAb (IL-12/IL-23) | Psoriasis | ns | 6/8 | Grace et al. [106] |